The present invention is directed to the controlled delivery of gonadotropin-releasing hormone (GnRH) agonists, preferably from a polymeric material that is implanted in the body. More specifically, the present invention relates to compositions comprised of a GnRH agonist, preferably histrelin, in a polymeric material that results in a desired and controlled delivery of a therapeutically effective amount of GnRH agonist in order to treat central precocious puberty (CPP).
There is a wide range of ages at which individuals normally start puberty. Girls usually develop breasts and then pubic hair between the ages of 8 and 13 years. Menstrual periods typically start at 12 to 13 years of age. Girls will often experience moodiness and become more irritable during puberty. Boys normally develop testicular enlargement and then pubic hair between the ages of 9 and 14 years. Underarm and facial hair, as well as deepening of the voice, typically occur between the ages of 13 and 16 years.
In the United States, an estimated one out of every 10,000 children suffers from central precocious puberty or premature puberty. This condition is evident when girls under the age of eight years and boys under the age of nine years develop signs of sexual maturity, such as the early onset of secondary sexual characteristics, increase in growth rate, advancement of skeletal age beyond chronological age. Signs or symptoms of CPP include, but are not limited to, the development of secondary sex characteristics such as breasts, testicle growth, or pubic hair.
True precocious puberty is the result of premature initiation of the function of the hypothalamic-pituitary axis. Premature release of the luteinizing hormone releasing hormone (LHRH) by the hypothalamus triggers secretion of the pituitary gonadotropin hormones. As a consequence, the gonads function at an inappropriately early age. Precocious puberty per se has many subdivisions: isosexual, heterosexual, gonadotropin-dependent (true precocious puberty), gonadotropin-independent, male-limited (familial testotoxicosis), cerebral, central, and idiopathic (unknown) precocious puberty. Precocious puberty is also known as familial testotoxicosis, gonadotropin-independent familial sexual precocity, and pubertas praecox.
In the majority of cases of precocious puberty, the cause is unknown. In some instances, the pituitary signals the ovaries and testicles to make female and male hormones at an earlier than usual time. In other cases, signs of puberty occur prematurely because of abnormalities in the ovaries, testicles, or adrenal glands. Tests are usually necessary to determine whether the cause of precocious puberty is in the brain or in another area of the body. Usually precocious puberty is idiopathic (unknown cause). In some instances, it is due to an endocrine disorder. Cerebral precocious puberty is associated with a brain abnormality, for example a tumor of the central nervous system, including hypothalamic hamartomas, infections, head trauma, hydrocephalus, or hypothyroidism. Precocious puberty may also be a feature of McCune-Albright syndrome, neurofibromatosis, Russell-Silver syndrome and disorders of the adrenal glands. Affected individuals may encounter psychological problems due to their accelerated growth and may feel alienated from their peers. They may exhibit increased aggressiveness and hyperactivity. Male-limited precocious puberty (familial testotoxicosis) is considered hereditary.
In females, the breasts start to develop before age 8, or menstruation occurs before age 10, and growth is rapid. In males, onset is before age 10; boys grow facial, underarm, and pubic hair; growth, including that of the penis, accelerates; the voice deepens; and behavior becomes more aggressive. Puberty may take place before age 3 in some children. Children with precocious puberty are taller than their peers. Since bone maturity is usually hastened in precocious puberty, closure of growth occurs prematurely, and patients are short in stature in adulthood. In isosexual precocious puberty, feminizing signs appear in girls, masculinization in boys. Heterosexual precocious puberty causes signs of masculine characteristics in girls and feminization in boys. Cerebral precocious puberty differs in cause but mimics true precocious puberty. Central precocious puberty is attended by changes that concern the central nervous system. Gonadotropin-dependent precocious puberty is marked by high gonadotropin levels in girls. Gonadotropin-independent precocious puberty usually affects boys, who have low levels of gonadotropin. Idiopathic precocious puberty is associated with EEG (Electroencephalogram) irregularities in girls. The cause of the unusual brain waves is unclear.
Treatments that affect the hypothalamic-pituitary-gonadal axis can effectively reduce hormones to pre-pubertal levels. This may arrest and prevent further development of secondary sex characteristics. Reduction of gonadotropins will allow for normal physical and psychological growth and development. Natural maturation occurs when gonadotropins return to pubertal levels following discontinuation of treatment.
GnRH (also referred to as luteinizing hormone-releasing hormone (LH-RH)) acts on the anterior pituitary gland to effect release of hormones that affect activity of the reproductive organs. GnRH is produced by the hypothalamic region of the brain and controls the reproductive cycle by acting on the anterior pituitary gland to affect release of luteinizing hormone (LH) and follicular stimulating hormone (FSH), which in turn act on the gonads to stimulate the synthesis of steroid hormones and to stimulate gamete maturation. The natural GnRH peptide is a hydrophilic decapeptide. Agonist analogs of GnRH may be used to control fertility, for example, low doses of GnRH agonists may stimulate ovulation and larger doses may block ovulation in females and suppress spermatogenesis in males through classic negative feedback principles.
Conventional treatment of CPP includes administration of GnRH agonists. Synthetic analogues of GnRH agonists are considered to be more effective than the natural agonists. Examples of GnRH agonists include, but not limited to, leuprolide (Lupron Depot®), goserelin (Zoladex®) and histrelin (Supprelin®), buserelin (Suprefact®), nafarelin (Synarel®) and triptorelin (De-capeptyl®, Trelstar Depot®). Many of these formulations involve monthly intramuscular injections of the drug. While usually effective in suppressing gonadotropin secretion, the monthly injections are painful, expensive, and inconvenient (monthly visits to the clinic nurse or physician). In some patients, gonadotropin suppression is not sustained by a monthly schedule of injections and the GnRH analog needs to be administered at 3-week or even 2-week intervals (1-3). For children, the daily dose of histrelin for treatment of CPP is typically about 10 μg/kg/day, which is equivalent to about 300 to about 600 μg histrelin per day.
Histrelin is a synthetic nonapeptide agonist of the naturally occurring GnRH. Initially the drug stimulates release of GnRH; however, chronic use desensitizes responsiveness of the pituitary gonadotropin, causing a reduction in ovarian and testicular steroidogenesis.
In view of the foregoing, a method for treating central precocious puberty and therapeutic compositions of GnRH agonists are provided.